KR20130099914A - Nalbuphine-based formulation and uses thereof - Google Patents

Abstract

An immediate release, oral pharmaceutical formulation comprising nalbuphine or a pharmaceutically acceptable salt thereof, and at least one hydrophilic granulation carrier, one hydrophilic binder, and one varnish.

Description

Nalbuphine-based formulations and uses thereof

The present invention relates to pharmaceutical preparations containing nalbuphine and its use for the treatment of pain.

Pain is a very common disease and one of the most frequent treatments for treatment.

Millions suffer from repetitive pain without receiving completely satisfactory treatment in improving symptoms.

Morphine derivatives have been widely used in the past for the treatment of pain, and their use has increased significantly over the last decade.

Nalbuphine is a semi-synthetic opiate derivative of receptor κ-agonists and receptor μ-antagonists belonging to phenanthrenes. This molecule is classified as an IIA class by the WHO. Its analgesic activity is equivalent to that of morphine and ten times stronger than that of pentazocin.

It is also used for anesthesia. Another advantage of this is that respiratory depression accidents and intoxication are low compared to other morphine derivatives.

Nalbuphine is a practically ideal analgesic by the following characteristics: rapid-acting, intense action, sparse inhibitory effect on the cardiovascular and respiratory system, and no toxic effect.

However, nalbuphine is well absorbed through the intravenous route (IV), so oral absorption is low and may change due to strong first-pass metabolism in the liver. Therefore, the nalbuphine forms on the market are manufactured for parenteral, intramuscular or rectal routes, with the disadvantages and disadvantages associated with these routes of administration.

Various pharmaceutical compositions containing nalbuphine have already been studied and described.

International application WO 82/03768 describes a nasal form consisting of a solution, suspension or ointment. There is no mention of oral forms.

International applications WO 98/0951 and WO 00/24386 describe transdermal patches consisting of the active ingredient and in particular nalbuphine chloride.

US Pat. No. 6,680,067 relates to controlled release GR pharmaceutical compositions in the form of oily suspensions comprising analgesic compounds which are nalbuphine in base or salt form, in the form of a mixture with injectable oils. The composition is characterized by the inclusion of microparticles in an oil suspension, said particle size being less than 100 μm, obtained using an ultra high energy mixer capable of obtaining particles having a particle size of less than 100 microns.

Russian patent RU 02/254852 describes nalbuphine chloride solution for injection.

International application WO 2007/025005 relates to a sustained release formulation comprising nalbuphine and one of its pharmaceutically acceptable salts, prepared for oral administration; This application describes a composition comprising a nalbuphine or a salt thereof and a sustained release system, the system comprising at least one hydrophilic compound, at least one crosslinker and at least one pharmaceutical diluent, or at least one hydrophilic A compound, at least one crosslinker, at least one pharmaceutical diluent and at least one cationic crosslinker different from the first cationic crosslinker, or at least one hydrophilic compound, at least one cationic crosslinker and at least one agent Chemical diluents.

Similarly, international application WO 2005/127683 relates to an essentially sustained release formulation of nalbuphine or a pharmaceutically acceptable salt thereof prepared for oral administration.

One of the aims of the present invention is to provide an oral form of nalbuphine with a rapid action close to the IV type of clinic and strong enough.

Since the immediate agents tested to date have exhibited low bioavailability due to the bolus effect causing saturation of the liver enzyme system, there are currently no immediate oral formulations, which is a release form with delayed intensive studies. Explain whether they are more focused on developing

Another difficulty with the use of oral nalbuphine lies in the particularly unpleasant strong taste of the active ingredient, which hinders its direct use in solution. This usually requires masking the taste with artificial sweeteners (flavours or coatings) that are detrimental to the immediate release of the active ingredient.

Therefore, research has shifted towards more sustained release formulations.

It is an object of the present invention to provide novel solid oral pharmaceutical formulations with rapid dissolution and bioavailability equivalent to nalbuphine in solute form.

The present invention therefore relates to an immediate release oral pharmaceutical preparation comprising nalbuphine or a pharmaceutically acceptable salt thereof and at least one hydrophilic granulation carrier, one or more hydrophilic binders and one gloss agent.

The term "hydrophilic" means any substance that is soluble or dispersible in water or a polar solvent.

1 shows various dissociation profiles of nalbuphine versus pH.
2 shows the ratio versus time of dissociated nalbuphine according to different operating conditions for the formulation of Example 5. FIG.

In a preferred embodiment of the invention, the pharmaceutical composition contains as active ingredient only nalbuphine or one of its pharmaceutically acceptable salts, preferably nalbuphine chloride.

The present invention provides that an oral pharmaceutical formulation having nalbuphine and at least one hydrophilic granulation carrier, one hydrophilic binder, and one gloss agent allows for the same good solubility and bioavailability as the nalbuphine solution for injection, administered orally. It was made from the unexpected discovery of the inventors. Therefore, the formulations of the present invention have the same efficacy as the injectable formulations in pain treatment and allow immediate release of the active ingredient for rapid treatment of pain.

Therefore, the present invention discloses an immediate release formulation for oral which can achieve a result comparable to that of an nalbuphine formulation for injection in an orally administered solution.

Pharmaceutical formulations with the expression “immediate release” include all pharmaceutical formulations in which the release and absorption rates do not change, particularly without any sustained release effect through any pharmaceutical manipulation. In the present invention, immediate release is achieved by the use of a pharmaceutically acceptable, at least one hydrophilic granulation carrier, one hydrophilic binder and one brightener, which do not substantially affect the release or absorption of the formulation. The expression "immediate-release" does not include agents modified for so-called "sustained", "extended" or "controlled release". Preferably, one immediate release form is one in which the amount of material released is at least 75% for 45 minutes (Guidance for industry, dissolution testing of immediate release solid dosage forms # 1997, FDA, CDER).

Preferably, the formulations of the present invention do not contain any crosslinking agent that can form a matrix that can be used for delayed release of the active ingredient in the presence of a hydrophilic compound. Crosslinking agent means homopolysaccharides such as guar gum, locust bean gum or cationic crosslinking agents.

The formulation is characterized by its in vitro release rate. Preferably, the immediate release formulation according to the invention has an in vitro release rate of at least 80% in 45 minutes.

The expression “nalbuphine or a salt thereof” according to the invention includes nalbuphine, chloride / HCl nalbuphine, esterified nalbuphine and their pharmaceutically acceptable salts, their complexes and derivatives. Preferably, nalbuphine of the present invention is in chloride form.

The term “pharmaceutically acceptable” refers to molecules and agents that do not cause any deleterious, allergic or side effects when administered to a mammal, especially a human.

Formulations of the present invention include a hydrophilic granulation carrier, a hydrophilic binder and a brightener. Preferably the hydrophilic granulation carrier, hydrophilic binder and varnish are selected to allow very rapid solvation of the active ingredient, which allows for rapid treatment of pain. Preferably, the hydrophilic granulation carrier, hydrophilic binder and brightening agent are chosen such that the release of the active ingredient does not change with pH change, which makes the preparation according to the invention independent of food intake causing a change in the pH of the stomach.

The formulations of the present invention result in near "flash" release of the active ingredient.

The expression "granulation carrier" includes all compounds which allow granulation of the pharmaceutical preparations according to the invention.

The term "granulation" refers to any process that allows the particles to crystallize or to convert the amorphous powder into larger solid aggregates that are somewhat resistant and somewhat porous.

Preferably, the hydrophilic granulation carrier is a polyol, for example mannitol, sorbitol, maltitol or xylitol, lactose, dicalcium phosphate, carbonate, for example calcium carbonate, potassium carbonate, magnesium carbonate or sodium carbonate, gluconate, Silica derivatives such as silicates such as magnesium aluminum silicate (Neusilin® UFL2), sugar crystals, starch derivatives, saccharose, polyvinyl pilolidone (PVP) or derivatives thereof, derivatives of cellulose such as methylcellulose , Hydroxypropyl methylcellulose or carboxymethylcellulose, polyethylene glycol or derivatives thereof, alone or in admixture.

More preferably, the hydrophilic granulation carrier of the present invention is mannitol, polyvinyl pyrrolidone or derivatives thereof, polyols, lactose cellulose derivatives such as methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, polyethylene glycol Or derivatives thereof and silica derivatives.

In one embodiment, the granulation carrier is mannitol.

The expression “at least one granulation carrier” indicates that the pharmaceutical formulation of the invention comprises one, two, three or more other granulation carriers.

The formulations of the present invention may also include at least one hydrophilic binder. The binders of the present invention are gum arabic or cragacan gum, gelatin, starch, maltodextrin, polyethylene glycol such as PEG 4000 or 6000, PVP or derivatives thereof, saccharose, glucose or sorbitol, polyols, lactose, carbomer Solution, a cellulose derivative such as methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose.

Preferably, the binder is PVP or derivatives thereof, polyols, lactose, cellulose derivatives such as methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, polyethylene glycol or derivatives thereof, gums such as Arabia Gum and Kragacan, and carbomer.

More preferably, the binder of the present invention is PVP.

The expression “at least one hydrophilic binder” indicates that the pharmaceutical formulation of the present invention may comprise one, two, three or more other binders.

The formulation also includes at least one varnish. The brightener according to the invention can be selected from silicon dioxide, magnesium stearate, colloidal anhydrous silica, sodium stearyl fumarate or talcum.

The expression "at least one varnish" indicates that the pharmaceutical formulation according to the invention may comprise one, two, three or more other varnishes. The brightener (s) are chosen such that they do not have any effect on the rate of release of the active ingredient (s).

In one preferred embodiment, the formulation comprises three different varnishes.

The formulations of the present invention may contain at least one other compound, such as, for example, excipients. Preferably, excipients that can be used in the formulations of the invention are selected from flavoring or taste-masking agents, sweetening agents, colorants and disintegrants such as polyvinylpyrrolidone. Flavors and taste-masking agents are particularly preferred to remove or weaken the unpleasant taste of nalbuphine.

The expression "flavourant" means any substance used in the pharmaceutical field that is added to a formulation to alter or mask the taste or aroma of the formulation. Sweeteners can also be used as natural or artificial with a sweet taste. Preferably, pharmaceutically acceptable sweeteners such as sugar substitutes (polyol derivatives, natural derivatives: stevia, etc.) and high intensity sweeteners (aspartame, cyclate, saccharin, etc.) are used.

The formulations of the present invention may further contain at least one film-forming agent, in particular forming an adhesive coating for increasing the stability of the formulation and masking the taste. Preferably, the film-forming agent is selected from cellulose derivatives, HPMC, polyethylene glycol derivatives, polyvinyl pyrrolidone derivatives, waxes, acrylic derivatives (eg Eudragit® L, RL, S) and carbomers. The film-forming agent is especially chosen to mask the taste without affecting the release rate of the active ingredient (s). The film former is preferably hydrophilic.

The preparations according to the invention particularly suggest combinations of excipients and oral release forms with a "flash effect". This "flash effect" release allows for very rapid release of the active ingredient. Indeed, with the preparations according to the invention, the amount of release material is at least 95% in 15 minutes. For conventional immediate release forms, the amount of material released is at least 75% in 45 minutes (Guidance for industry, dissolution testing of immediate release solid dosage forms # 1997, FDA, CDER).

In one preferred embodiment, the preparations according to the invention further comprise:

At least one disintegrant;

At least one excipient.

The preparations according to the invention can be completed by excipients, for example by compresses.

In some preferred embodiments, the pharmaceutical formulation of the present invention comprises less than 30% by weight nalbuphine, preferably 4-30% by weight and more preferably 18-22% by weight, based on the total weight of the formulation.

In some preferred embodiments, the pharmaceutical preparations according to the invention comprise at least 45% by weight, preferably 45-70% by weight, and more preferably 55-65% by weight of the hydrophilic granulation carrier, based on the total weight of the preparation. Contains%

In some preferred embodiments, the pharmaceutical formulation of the present invention comprises less than 10% by weight, preferably 2-10% by weight and more preferably 4-8% by weight of the hydrophilic binder, based on the total weight of the formulation.

In some preferred embodiments, the pharmaceutical formulations of the present invention comprise less than 10% by weight, more preferably 0.9-7% and more preferably 2-3% by weight, based on the total weight of the formulation.

In another preferred embodiment of the invention, the formulation is in particular:

Nalbuphine from 4 to 30% by weight,

Lactose 45-70% by weight,

PVP 2-10 wt%; And

-0.9 to 7% by weight of at least one brightener, complete with excipients.

The pharmaceutical formulation of the present invention is for oral administration. The pharmaceutical preparations of the invention are preferably solid. The solids of the present invention are in particular selected from tablets, granules, pellets, micro-granules, hard capsules, soft capsules, sublingual tablets, lozenges tablets. The form of the preparation according to the invention is particularly preferred for soft capsules or tablets to be swallowed directly by the user. This mode of administration allows the user to digest the preparation sufficiently quickly without experiencing discomfort by the unpleasant taste of nalbuphine.

The technique used to obtain the solids of the preparations according to the invention is by any method known to those skilled in the art to obtain solid preparations. In particular, these methods can be selected from the techniques of wet and dry granulation, direct pressing, fluidized bed granulation, film-coating and spray drying.

The formulations of the present invention allow particularly good nalbuphine bioavailability. "Good bioavailability" means that a sufficient proportion of nalbuphine contained in the formulation will work effectively in the body compared to the amount absorbed and provide the desired therapeutic effect.

In one specific embodiment, the present invention relates to such a pharmaceutical formulation for use as a pharmaceutical product in the treatment of pain, in particular in the treatment of non-chronic pain.

The advantage of the mild-release according to the invention for this use is that they allow for the rapid treatment of pain, as opposed to sustained-release preparations.

Pain that can be treated with the pharmaceutical formulations of the invention may be due to any cause, for example, by treatment of opioid poisoning, by cancer, by autoimmune diseases, by infection and by tumors and the like. It may be due to pain.

Preferably, the pain treated with the formulation of the present invention is caused by the treatment of opioid poisoning.

In one preferred embodiment, the present invention relates to the use of such pharmaceutical agents as drugs in the treatment of opioid intoxication.

Example

Preparation of Pharmaceutical Formulations in Tablet Form

Compositions and methods for preparing nine types of formulations (Examples 1, 2, 3, 4, 5, 6, 7, 8 and 9) It is described below.

Example  One : 30 mg  refine

expression

This formulation was obtained according to the following protocol:

Weighing of the raw material (balance);

-Mixing nalbuphine, purified water and povidone (spiral stirrer);

Solubilizing and complexing the mixture (GPCG3 fluidized bed, Wurster and peristaltic pump);

Mannitol is coated with the mixture and the coated mannitol is dried to obtain granules;

Screening granules (sieve scale size diameter 600 μm, oscillating screen, sieve scale 630, 500 and 400 μm);

-Adding talc to polish the granules (Erweka mixer 8L cube vessel);

Mixing and polishing the granules with mannitol, povidone, crospovidone, anhydrous colloidal silica, sodium stearylfumarate (Erweka mixer and 8 L cube vessel);

Obtaining tablets from the mixture (SVIAC RP2080 rotary compactor, 13 mm dice).

Example  2 : 30 mg  refine

expression

This formulation was obtained according to the following protocol:

Weighing of the raw material (balance);

Nalbuphine, talc and a mixture of Tablettose® and Avicel®;

Mixing povidone and purified water to obtain a binder solution;

Spraying the binder solution onto the first mixture to obtain granules;

Drying the obtained granules in an air fluidized bed;

Gloss by adding magnesium stearate and anhydrous colloidal silica;

XL, homogenized and merged into granules

Direct compression of the mixture;

Preparing film-coated suspensions: Sepifilm® LP014 and alcohols;

-Film coating and drying

Example  3 : 10 mg  refine

expression

This formulation was obtained according to the following protocol:

-Measuring the weight of the raw material (balance);

Cube mixer (8 L), 5 min homogenization at 150 rpm (Nalbuphine, Avicel® PH200, talc, Aerosil®200, Tablettose®80 and PVP K30);

The mixture was polished with magnesium stearate at 150 rpm for 1 minute;

Compressing the mixture on a Korsch instrument (G009, diameter 9);

Preparation of a coating solution on a magnetic plate with Sepifilm LP014 and purified water;

Aqueous coating of the compressed mixture in LAF GPCG 1.

Example  3-1 : 50 mg  refine

expression

This formulation was obtained according to the following protocol:

-Measuring the weight of the raw material (balance);

Cube mixer (8 L), homogenized (Nalbuphine, Avicel® lactose, PVP CL and flavoring agent) at 150 rpm for 5 minutes;

The mixture was polished with magnesium stearate at 150 rpm for 1 minute;

Compressing the mixture in Korsch (G009, diameter 9);

Preparation of a coating mixture on a magnetic plate with Sepifilm IR 777, purified water and flavoring agent;

Aqueous coating of the compressed mixture in LAF GPCG 1.

Example  4 : 10 mg Pellets

expression

This formulation was obtained according to the following protocol:

-Measuring the weight of the raw material (balance);

Dispersing PEG 400, nalbuphine, sucralose, taste masking agent, caramel flavoring agent in ethanol (stirrer);

Injection of this mixture into Neusilin UFL2 (mixer and peristaltic pump), calibration (vibration rotor) and drying (fluidized bed dryer, top spray);

-Adding PVP 30 and purified water and granulating the resulting mixture (fluidized bed dryer, top spray vessel);

-Calibrate pellets (vibrator rotator and 800 μm sieve scale);

Sepifilm LP104 and water added and dried to coat the particles (fluidized bed granulator, Wurster vessel);

-Coating the coated particles with talc (cubic mixture).

Example  5 : 30 mg  refine

expression

The formulation was obtained according to the following protocol:

Weighing of the raw material (balance);

-Mixing nalbuphine, talc and Tablettose® (granulation carrier);

Combining binder water with PVP K30 to obtain a binder solution;

Spraying the binder solution onto the first mixture to obtain granules;

Drying the obtained granules in an air fluidized bed;

-Avicel®, Aerosil® and Polyplasmon XL are mixed, homogenized and merged into granules;

Gloss by adding magnesium stearate and anhydrous colloidal silica;

Direct compression of the mixture;

Preparing film-coating suspensions: Sepifilm® LP014 and purified water;

-Film coating and drying.

Example  6 : Other Granulation Carrier  Of tablets with agents having Disintegration  Comparative study of time

Replace Tablettose 80 with Calcium Glycerophosphate

The amount of raw material is about the same as the amount of raw material of the composition of the examples. Only granulation carriers changed in the composition of the coated tablets.

Tablets according to the composition and tablets according to the composition of Example 5 were tested.

They were constantly stirred in the medium maintained at 37 ° C. (± 0.5 ° C.) in the dissociation apparatus. Samples were taken at 5, 10, 15, 30 and 60 minutes with a piston pump and sample collector. These samples were analyzed by HPLC.

Dissociation conditions are as follows:

-Device 1 USP <711> (device with basket)

Rotation speed: 50 rpm.

Dissociation medium: HCl 0.1N

Volume: 500 MI.

Test sample: 30 mg tablets.

The disintegration time of such coated tablets exceeds 8 hours 30 minutes.

Disintegration time under the same operating conditions for Example 5 is 5-8 minutes.

Example  7 : Other pH Dissociation Studies in the Medium

Working conditions were the same as those used in the previous comparative studies.

During this study, several media with different pH were tested: HCl 0.1N, pH 1.2, 4.5 and 6.8 (FIG. 1).

It has been shown that the pH and properties of the medium do not substantially affect the dissociation profile of the formulation.

Example  8 : Solubility of Formulation

The increase in bioavailability of the formulation was evaluated in relation to dissociation of the pharmaceutical form.

Immediate release forms are those in which the amount of substance released is at least 75% in 45 minutes (Guidance for industry, dissolution testing of immediate release solid dosage forms 1997, FDA, CDER). Dissociation profiles of the different formulations were obtained via dissociation measurements.

For this purpose, a dissociation device equipped with an impeller was used. The formulation was constantly stirred at 50 rpm in a vessel containing 500 ml purified water and maintained at 37 ° C.

Samples were taken at the scheduled time of 1 hour and then analyzed by HPLC with ultraviolet detection at wavelength 285 nm.

Example  Formulation of 1

Example  Formulation 3

Example  4, formulation

As shown in the results of these experiments, the other formulations described were specifically developed to achieve very fast dissociation times to meet the definition.

Example  9 Pharmacokinetic Studies

Open I stage trials (both arms) were performed with the following formulations:

Oral formulation of Example 1 (30 mg tablet)

Oral administration of nalbuphine (IV)

Attempts were made by administering a single dose to 8 fasting healthy male volunteers (4 volunteers per arm). Various coefficients were measured: Tmax (time the maximum amount of formulation dissolved), Cmax (maximum amount of dissociated formulation) and AUC (concentration / time, area under the curve). The following results were obtained:

Based on average Tmax Formulation Tmax (h) 30 mg solid oral form of Example 1 1.25 Oral solution type IV administered 30 mg (comparative) 0.75

Tmax was found to be slightly time-shifted in comparison to the liquid solution of nalbuphine for the solid oral form according to the invention.

Pharmacokinetic coefficients, arithmetic mean Formulation Cmax (ng / mL) Tmax (h) AUCt (ng / mL * h) AUCinf (ng / mL * h) 30 mg solid oral form of Example 1 7.91 1.21 30.93 38.08 Oral solution type IV administered 30 mg (comparative) 9.34 0.71 33.06 39.07

Slightly different from Tmax, it was found that the pharmacokinetic coefficients are compatible with the solid and oral solutions of the present invention.

Relative bioavailability (based on normalized dose, arithmetic mean value) Formulation Cmax ratio AUCt Ratios AUCinf Ratios Oral Form of Example 1 30 mg /
Oral solution 30 mg (comparative) 0.85 0.94 0.97

Pharmacokinetic Coefficient, Geometric Mean Formulation Cmax (ng / mL) AUCt (ng / mL * h) AUCinf (ng / mL * h) 30 mg solid oral form of Example 1 6.72 26.22 31.80 Oral solution 30 mg (comparative) 8.63 29.72 34.47

Relative Bioavailability  (Normalized dose basis, geometric mean value) Formulation Cmax ratio AUCt ratio AUCinf ratio 30 mg solid oral form of Example 1
Oral solution 30 mg (comparative) 0.78 0.88 0.92

These data are close to those observed in the oral form tested in Form IV administered orally; A slight difference was observed for Tmax but the release obtained is very rapid, indicating that this is not detrimental to the desired therapeutic effect.

Example  10 : Comparative Study on Reference Oral Solutions

The data from these studies were compared with those described in the references. Based on the linearity of the dose, the following values were obtained.

Pharmacokinetic Coefficients (arithmetic mean-normalized dose 30 mg ) Formulation Cmax (ng / mL) AUCt (ng / mL * h) AUCinf (ng / mL * h) 30 mg solid oral form of Example 1 7 .91 30.93 38.08 Oral solution of nalbuphine 30 mg 6.88 30.93 34.25

Relative Bioavailability (arithmetic mean-normalized dose 30 mg ) Formulation Cmax ratio AUCt Ratios AUCinf Ratios 30 mg solid oral form of Example 1
30 mg solution (comparative) 1.15 1 .00
1.11

Pharmacokinetic Coefficient (Geometric Mean-Normalized Dose 30 mg ) Formulation Cmax (ng / mL) AUCt (ng / mL * h) AUCinf (ng / mL * h) 30 mg oral form of Example 1 6.72 26.22 31.80 Oral solution of nalbuphine 30 mg 6.24 28.15 31.57

Relative bioavailability (dosage 30 mg Geometric mean normalized to 30 mg / solid solid oral form of Example 1
Oral solution 30 mg (comparative) 1.08 0.93
1.01

For geometric mean values, the bioavailability mentioned for oral solutions of nalbuphine is compatible with that observed in solid form.

Example  11 : Comparative Study on Oral Reference Solution

A second Phase I study was performed on the oral formulation of Example 2, on one arm (30 mg tablets).

The study was completed by administering a single formulation of 30 mg of nalbuphine to 12 healthy volunteers who fasted. Various coefficients were measured: Tmax (time after the maximum amount of formulation dissolved), Cmax (maximum amount of dissolved formulation) and AUC (area under the concentration vs. time curve).

The observed data was compared with the data obtained during the study of Example 9 for the oral administration of nalbuphine (IV).

Also observed values were similar. The values of Cmax and AUC were similar. Tmax was shorter than that of the formulation according to Example 2.

Claims (18)

An immediate release oral pharmaceutical formulation comprising nalbuphine or a pharmaceutically acceptable salt thereof, and at least one hydrophilic granulation carrier, one hydrophilic binder, and one varnish. The pharmaceutical preparation according to claim 1, which contains as an active ingredient only nalbuphine or one of its pharmaceutically acceptable salts, preferably nalbuphine chloride. The hydrophilic granulation carrier of claim 1 or 2, wherein the hydrophilic granulation carrier is selected from the group consisting of mannitol, polyvinyl pyrrolidone or derivatives thereof, polyols, lactose, cellulose derivatives, polyethylene glycols or derivatives thereof and silica derivatives. Pharmaceutical preparations. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the hydrophilic granulation carrier is lactose. The hydrophilic binder according to any one of claims 1 to 4, wherein the hydrophilic binder is selected from the group consisting of polyvinyl pyrrolidone or derivatives thereof, polyols, lactose, cellulose derivatives, polyethylene glycols or derivatives thereof, gums and carbomers. Pharmaceutical preparations. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the hydrophilic binder is polyvinylpyrrolidone. The pharmaceutical formulation of claim 1, wherein the brightener is selected from the group consisting of silicon dioxide, magnesium stearate, anhydrous colloidal silica, sodium stearyl fumarate and talcum. 8. A method according to any one of the preceding claims, comprising at least 45% by weight, preferably 45-70% by weight, more preferably 55-65% by weight, based on the total weight of the formulation. Pharmaceutical formulations. 9. A medicament according to any one of claims 1 to 8, comprising up to 10% by weight of hydrophilic binder, preferably from 2 to 10% by weight, more preferably from 4 to 8% by weight, based on the total weight of the formulation. Pharmaceutical preparations. The pharmaceutical composition according to any one of claims 1 to 9, comprising 10% by weight or less, preferably 0.9 to 7% by weight, more preferably 2 to 3% by weight, based on the total weight of the formulation. Formulation. The pharmaceutical composition according to any one of claims 1 to 10, comprising up to 30% by weight of nalbuphine, preferably 4 to 30% by weight, more preferably 18 to 22% by weight, based on the total weight of the formulation. Formulation. The method according to any one of claims 1 to 11, further comprising:
One or more disintegrants; And optionally
Pharmaceutical formulations comprising one or more excipients. 12. The method according to any one of claims 1 to 11,
Nalbuphine 4-30% by weight;
Lactose 45-70 wt%;
PVP 2-10 wt%; And
Pharmaceutical formulations comprising from 0.9 to 7% by weight of at least one varnish. The pharmaceutical formulation of claim 1, which is in solid form. The pharmaceutical formulation according to claim 14, which is in the form selected from the group consisting of tablets, granules, pellets, micro-granules, capsules and lozenges. The pharmaceutical formulation of claim 1 for use in the treatment of pain. The pharmaceutical formulation of claim 16, wherein the pain is caused by the treatment of opioid poisoning. The pharmaceutical formulation of claim 1 for use in the treatment of opioid poisoning.

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